Intervertebral disc (IVD) degeneration is a debilitating disorder implicated in the pathogenesis of chronic low back pain, a leading cause of global disability and a contributor to the opioid crisis in the USA. However, the interaction between IVD degeneration and the nervous system that leads to chronic low back pain is not well understood. Further, while both spine impairments and chronic pain conditions are more common in women, there are almost no studies examining the possible effects of sex on the relationship between IVD degeneration and nervous system changes in the setting of chronic low back pain. The overall goal of the proposed research is to determine how IVD degeneration, pain across sensory modalities, and nervous system gene expression changes interact in the pathogenesis of chronic low back pain, and how these complicated relationships may differ between males and females. The proposed studies apply a unique rat model to identify novel targets for non-opioid therapies for chronic low back pain, that may enable more precise therapeutic targeting of the pathologic changes in chronic low back pain, without the risks of opioid usage. Aim 1 will determine how sex and IVD injury interact in the induction of structural, morphological, and biomechanical changes in the IVD in degeneration. Aim 2 measures sex differences in pain at the behavioral level by testing for changes in pain sensitivity across multiple sensory modalities. Aim 3 evaluates the transcription-level changes in the nervous system that likely play a significant role in the pain sensitivity measured in Aim 2, in order to identify possible therapeutic targets. This project is significant because of the translational potential to the highly clinically significant problem of discogenic back pain. The approach is innovative because it investigates the influence of sex on the pathogenesis of chronic back pain originating from intervertebral disc injury and degeneration. Improved understanding of the influence of sex on intervertebral structure, morphology, and biomechanics, and via what molecular pathways they may induce a chronic pain state in the nervous system may enable better-targeted therapies to replace the use of opioid analgesics for chronic low back pain. Such knowledge would be highly significant to the fields of orthopaedics, neuroscience, and medicine, as clarifying these interactions may improve current treatments and reduce the global suffering from chronic back pain. This fellowship application will also fund MD/PhD studies of a highly promising clinician- scientist with commitment to the application of complementary and integrative health strategies to manage chronic low back pain.